Research Article: IL-4 Induced Innate CD8+ T Cells Control Persistent Viral Infection

Date Published: October 9, 2015

Publisher: Public Library of Science

Author(s): Ara Lee, Seung Pyo Park, Chan Hee Park, Byung Hyun Kang, Seong Hoe Park, Sang-Jun Ha, Kyeong Cheon Jung, Barbara Sherry.


Memory-like CD8+ T cells expressing eomesodermin are a subset of innate T cells initially identified in a number of genetically modified mice, and also exist in wild mice and human. The acquisition of memory phenotype and function by these T cells is dependent on IL–4 produced by PLZF+ innate T cells; however, their physiologic function is still not known. Here we found that these IL-4-induced innate CD8+ T cells are critical for accelerating the control of chronic virus infection. In CIITA-transgenic mice, which have a substantial population of IL-4-induced innate CD8+ T cells, this population facilitated rapid control of viremia and induction of functional anti-viral T-cell responses during infection with chronic form of lymphocytic choriomeningitis virus. Characteristically, anti-viral innate CD8+ T cells accumulated sufficiently during early phase of infection. They produced a robust amount of IFN-γ and TNF-α with enhanced expression of a degranulation marker. Furthermore, this finding was confirmed in wild-type mice. Taken together, the results from our study show that innate CD8+ T cells works as an early defense mechanism against chronic viral infection.

Partial Text

Conventional T cells take on naive phenotypes when they emigrate out from the thymus, whereas innate T cells from the thymus are phenotypically of the effector/memory form [1]. Compared with conventional T cells, these innate T cells, such as natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and H2-M3-specific T cells, are selected by interaction with hematopoietic cells rather than thymic epithelial cells, and their development is dependent on IL–15 and the SAP (SLAM-associated protein) signaling pathway [1]. Moreover, most innate T cells express T cell receptors (TCRs) specific for MHC class Ib molecules [1,2].

Over the course of viral infection there may be a limited time period during which the host system can eliminate the virus [22]. When viruses are not eliminated within this period of time, virus-specific CD8+ T cells are exhausted via PD–1 (programmed death 1) and its ligand, PD-L1 interaction, resulting in a chronic infection [23]. In this study we demonstrated that IL-4-induced innate CD8+ T cells are able to effectively control the chronic viral infection. For this, we first compared T-cell responses to chronic viral infection induced by LCMV CL–13 in CIITATg and wild-type C57BL/6 mice. The immune system of the CIITATg mouse resembles that of humans with respect to MHC class II expression in both thymic epithelial cells and thymocytes making it a suitable model [24–27]. Thus, PLZF+ T-T CD4+ T cells are generated in response to TCR signals from the MHC class II/peptide complex expressed on thymocytes [15,27,28] and provide IL–4 for the development of IL-4-induced innate CD8+ T cells [14]. When mice were infected with CL–13, CIITATg mice were able to control viral titers below detection levels in selected tissues such as the spleen and serum within a month, whereas wild-type mice succumbed to persistent infection. Furthermore, the ability of CIITATg mice to control the virus was dependent on IL-4-induced innate CD8+ T cells as CIITATg and control mice did not show a difference in serum viral titers on the IL–4 deficient background, which causes a lack of intrathymic generation of IL-4-induced innate CD8+ T cells. Moreover, adoptive transfer of LCMV-specific IL-4-induced innate CD8+ T cells into wild-type hosts further confirmed the crucial role of these innate T cells as the primary effector mechanism for viral control. We also demonstrated that wild-type BALB/c mice, which have abundant IL-4-induced innate CD8+ T cells, exhibit notably enhanced anti-viral CTL responses compared with CD1dKO BALB/c mice, which only possess a very small fraction of these cells. As expected, expression level of Eomes and innate CD8+ T cell marker (CD44 and CXCR3) was higher in virus-specific CD8+ T cells wild-type mice, as compared to those of CD1dKO BALB/c mouse (Fig 8B), while we could not found any difference in LCMV NP118-specific CD8+ T cell numbers in these mice (Fig 8A). Considering the results from P14 cell adoptive transfer and CL–13 infection (Fig 6), these data favor the idea that IL-4-induced innate CD8+ T cells in a wild-type BALB/c host contributed to reduce CL–13 viral load compared with CD1dKO mice, although the genetic perturbation in CD1dKO mice is not specific for the innate CD8+ T cell population.




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